CBX1 mutations cause a neurodevelopmental syndrome due to heterochromatin organizational alterations

The heterochromatin protein 1 (HP1) family of proteins represents an essential structural component of heterochromatin formation and organization. There are three HP1 proteins (HP1, HP1{beta}, and HP1{gamma}), and HP1{beta} is the only essential HP1 protein during mammalian development. Here we report a neurodevelopmental disorder due to missense mutations in the CBX1 gene which encodes HP1{beta}. Two unrelated individuals were found to have de novo missense mutations in CBX1. Their clinical features include developmental delay, hypotonia and autistic features, suggesting the importance of HP1{beta} in neuronal function. Identified mutations are in a known functional domain, chromodomain, and the identified mutations abolished HP1{beta}-chromatin interactions. Our transcriptome and epigenome analyses revealed that reduced HP1{beta} chromatin affects gene expression of H3K27me3 marked genes, suggesting the importance of HP1{beta} in facultative hetrochromatin organization during human development. This diagnosis represents the first genetic disorder due to germline mutations in genes encoding HP1 proteins.